Oxalipatinum preparation packaging

ABSTRACT

Flexible impervious bag for medical use containing a pharmaceutical preparation of liquid oxaliplatinum said flexible bag is constructed from plastic materials, with the proviso that any portion to the bag in direct contact with said pharmaceutical preparation of liquid oxaliplatinum does not contain polyvinylchloride-based plastic material.

The invention concerns a pharmaceutical preparation of oxaliplatinumpackaged in a container, preferably in a sealed soft (flexible) bag formedical use.

The optically active complex of platinum,cis-oxalato(trans-1-1-diaminocyclohexane) platinum(II), under itsinternational nonproprietary name (INN) “oxaliplatinum”, is known topossess anti-tumor properties and its preparation was described in thepatent U.S. Pat. No. 4,169,846.

Oxaliplatinum, like other platinum complexes such as Cisplatin orCarboplatin, is used as an antineoplastic, cytostatic agent for thetherapeutic treatment of various types of cancer. These include, interalia, cancer of the colon, ovaries, tipper respiratory passages orepidermal (skin) cancers as well as germ cell tumors (testes,mediastinum [interpleural space], pineal gland etc.). The use ofoxaliplatinum is particularly appropriate for the treatment of coloncancers that are resistant to pyrimidines, of small cell lung cancers,non-Hodgkin lymphomas, breast cancers, cancers of the upperrespiratory-digestive passages, malignant melanomas, liver carcinomas,uro-epithelial cancers, cancers of the prostate etc.

International Patent Application WO 96/04904 describes a pharmaceuticalpreparation of oxaliplatinum in aqueous solution. This preparation hasthe advantage of obtaining a ready-to-use, injectable solution ofoxaliplatinum that is simpler and more reliable in use and lessexpensive to manufacture than a preparation starting with a lyophilisate(freeze-dried substance). It has a chemical purity (no racemisation) andtherapeutic activity equivalent to or greater than those obtained bystarting with a reconstituted lyophilisate.

This pharmaceutical preparation was stored in bottles made of neutralglass for pharmaceutical use under an inert gas atmosphere. However,such bottle packages, although appropriate for long-term storage of thepharmaceutical preparation, are unsuitable for containing thispreparation during administration by perfusion.

Flexible bags consisting of a material based on polyvinylchloride (PVC)are used during perfusion procedures of liquid preparations of platinumcomplexes other than oxaliplatinum, such as cisplatin or carboplatin.

However, and in contrast to what has been observed for liquidpreparations of cisplatin and carboplatin, it has been found thatparticularly because of their greater chemical sensitivity,pharmaceutical preparations of oxaliplatinum in aqueous solution cannottolerate being in contact with PVC-based materials, nor can, they betransported and/or stored in containers, especially flexible bags basedon these materials.

The aim of the present invention is to provide liquid pharmaceuticalpreparations of oxaliplatinum that can not only be stored for a longperiod of time without any detectable loss of quality but can also beused in particular for perfusion procedures without any need for thenursing personnel to perform an operation to decant liquidpharmaceutical preparations.

For this purpose, the present invention concerns a liquid pharmaceuticalpreparation of oxaliplatinum as set forth in the appended claims.

The invention will be set out below with the help of the Drawings inwhich

FIG. 1 shows a cross-sectional view of the envelope of the flexible bagused in the invention;

FIG. 2 shows a cross-sectional view of the flexible hag used in theinvention;

FIG. 3 shows a comparison graph of the liquid phase water permeabilityfirstly of PVC and secondly of a suitable construction material for theenvelope of the flexible bag used in the invention, before and after asterilisation procedure;

FIG. 4 shows a comparison graph of the vapour phase water permeabilityof various suitable construction materials for the envelope of theflexible bag used in the invention, before and after a sterilisationprocedure;

FIG. 5 shows a comparison graph of the oxygen permeability of varioussuitable construction materials for the envelope of the flexible bagused in the invention, before and after a sterilisation procedure;

FIG. 6 shows the pH variation over time of a preparation according tothe invention; and

FIG. 7 shows the pH variation over time of a liquid pharmaceuticalsolution of oxaliplatinum stored in a glass bottle under an inert gasatmosphere.

The pharmaceutical preparation of oxaliplatinum according to the presentinvention is stored, then used directly, in a flexible bag constructedfrom plastics materials chosen from among polyethylenes (PE),polypropylenes (PP), polyethyl and polyvinyl acetates polyamides (PA)and polyisobutyls (PIB). Latex (rubber) can also be used.

As shown in FIG. 1, the envelope of the bag preferably has a multi-layerstructure. More preferably, the internal layer in direct contact withthe pharmaceutical preparation consists of PP and the external layer orpossible intermediate layers can consist of any of the above-mentionedplastic. The external layer or the possible intermediate layers can evenconsist of PVC, the oxaliplatinum not being in direct contact with thismaterial.

As shown in FIG. 2 and according to a particular embodiment of theinvention, the flexible bag can consist of welded sheets of multi-layermaterials. Preferably the flexible bay can consist of at least twosheets welded together. More preferably, this bag can consist of twowelded sheets of multi-layer sheet materials comprising, one film of11-amino-undecanoic acid (PA 11) bonded by at least one of its surfacesto a film of PP by the use of a polyolefin film the PP films forming theinternal wall of the leakproof flexible bag.

The flexible bag of the invention preferably consists of a materialcomprising 70% of PP and 30% of PA 11 and commonly called V90.

Astonishingly it has been found, during a physico-chemical studyperformed before and after the sterilisation procedure and comparing theliquid phase water permeability properties of flexible bag envelopesconsisting firstly of PVC and secondly of V90, that the bags based onV90 material constitute an excellent barrier to water loss generally dueto evaporation. This property is not found in the classical PVC bags,not even those using PVC as a constituent of the inner layer.

The results of this study are shown diagrammatically by the graph ofFIG. 3.

During a second study comparing the vapour phase water permeabilityproperties of PVC and various construction materials for the flexiblebags used in the invention, the material V90 proved to be the mostleak-tight (impervious) as shown by the diagram in FIG. 4.

Such properties of imperviousness to water in its two forms, liquid andvapour, are extremely important when contemplating the use of such amaterial for the construction of the flexible bags used for theinvention. In fact, the almost zero losses of water guarantee themaintenance of an almost constant concentration of the pharmaceuticalpreparations of oxaliplatinum over time. Excessive packaging of theenvelope of the bag used for the invention is thus unnecessary.

The impermeability to oxygen of the V90 material was also studied andcompared to that of PVC, and proved to be at a far superior level. Theresults of studied comparative study are shown diagrammatically in FIG.5.

This property of impermeability to oxygen is very important in view ofthe sensitivity of oxaliplatinum to oxidising substances, thedegradation products generated during such oxidation generally beinginactive from the pharmacological point of view and may even be toxic tothe organism. This property is very suitable during the use of theflexible bag, which has the advantage compared to glass bottles of notneeding the presence of an inert gas atmosphere.

The V90 material also affords the advantage from the ecological point ofview of being recyclable and reusable in another form, which is not thecase with PVC.

Another attractive aspect of the use of the aforementioned materials,particularly PP (V90), lies in the ability to make leak-tight welds veryeasily. In this way it is possible to obtain flat compartmented bags.This property is not achievable with a PVC material, which requires theuse of connectors to communicate between the various compartments.Unfortunately these connectors are a source of leaks, which is notobserved in the case of bugs made of PP (V90).

These compartments can be multiple so as to allow the mixing ofdifferent solutions. These compartments can contain the solution alreadyready for use, at the right dose, and can be withdrawn or used directlyby the medical personnel without the risk of error.

The aforesaid materials, particularly PP (V90), also have the advantageof withstanding high temperatures better. This is particularlyattractive during the sterilisation of flexible bags containing asolution of oxaliplatinum by autoclave. This sterilisation is muchsimpler because the exposure tire can be reduced by increasing thetemperature.

The liquid oxaliplatinum solution contained in the bags preferably has aconcentration between 1 and 8 mg/ml. According to one particularembodiment of the invention the oxaliplatinum concentration lies between1 and 5 mg/ml at a pH between 4 find 7, ideally between 4.5 and 6.0.

According to one particular embodiment of the invention theconcentration of oxaliplatinum in the preparation contains at least 95%of the initial concentration and has a clear, colourless appearance freefrom precipitate after storage during a pharmaceutically acceptableperiod.

A test of the stability of the liquid solution of oxaliplatinum (TanakaK. K., Batch I.o 92 TO 34) was carried out. To do this, 100 ml bagsconsisting of PA 11/PP 60/140 and measuring 13.0×12.5 cm were used. Thehags contained 200 m, of oxaliplatinum at a concentration of 2 mg/ml,i.e. 100 ml of liquid Oxaliplatinum solution per bag. This test wasperformed over a total or 12 weeks in accordance with the sampling plan.The bags were subjected to what are called accelerated storageconditions at a temperature of 40° C. and a relative humidity (R11) of75%.

The results of this accelerated stability study are summarised in Table1

Kinetic parameters Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 12 6Months 12 Months Appear- Clear, Clear, Clear, Clear, Clear, Clear,Clear, Clear, Clear, ance of colourless colourless colourless colourlesscolourless colourless colourless colourless colourless the solutionL-OHP 99.7 100.1 100.0 100.9 99.3 97.7 99.3 98.9 98.5 titre/ standard(%) Oxalic <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% acidtitre (%) Visible 0.10 0.60 0.50 0.50 0.48 0.45 0.40 0.5 0.6 impurities(%) pH 5.56 5.10 5.24 5.22 NM 5.23 5.35 5.20 5.30 NM = Not measured

In a surprising manner the liquid solution of oxaliplatinum packed in aflexible bag is stable for a period extending to more than three months,and even to more than six months.

Astonishingly, this liquid solution of oxaliplatinum packed in aflexible ban appears to remain stable for at least one year.

The appearance of the solution was observed for twelve months, and toour great astonishment showed clarity and the absence of coloration overthe whole of this period. Analysis of the concentrations was performedby high pressure liquid chromatography (HPLC=High Performance LiquidChromatography).

As far as the concentration of oxaliplatinum is concerned, a statedquantity lying between 95 and 105% was obtained, taking into account thelimit of resolution of the system. As far as the determination of oxalicacid is concerned, the maximum limit is 0.5% by the HPLC method.

The maximum percentage of apparent impurities determined in the same waywas 2%.

FIG. 6 shows the development of the pH over 12 weeks. This pH liesbetween 4.7 and 5.9, and varies very little with time, which is goodproof that the oxaliplatinum solution remakes stable in this type ofbag. This system shows a stability analogous to that observed for asolution of oxaliplatinum subjected to the same conditions and packed ina glass bottle, as FIG. 7 shows.

All of the above results show consistently that pharmaceuticalpreparations of oxaliplatinum can be stored in flexible bags for a longperiod without any chemical degradation of the oxaliplatinum beingobserved, from the moment they are no longer in direct contact withPVC-based material. Because of the flexibility of the materials of whichthe bags consist, such preparations are ready to the used fortransfusion procedures without any decanting operation being necessary.

1. Flexible impervious bag for medical use containing a pharmaceuticalpreparation of liquid oxaliplatinum, said bag having a multi-layerstructure comprising an outer envelope and/or internal layers, with theproviso that any portion of the bag in direct contact with saidpharmaceutical preparation of liquid oxaliplatinum does not containpolyvinylchloride-based plastic material, wherein said flexible bagconsists of two welded sheets of multi-layer sheet material comprisingas its outer envelope a film of polyamide of 11-amino-undecanoic acidbonded by at least one of its surfaces to a film of polypropylene bymeans of a film of polyolefin, the polypropylene film forming theinternal layer of the flexible bag.
 2. Flexible impervious bag formedical use containing a pharmaceutical preparation of oxaliplatinumaccording to claim 1, wherein the concentration of oxaliplatinum in thepharmaceutical preparation is between 1 and 8 mg/ml.
 3. Flexibleimpervious bag for medical use containing a pharmaceutical preparationof oxaliplatinum according to claim 1, wherein the concentration ofoxaliplatinum in the pharmaceutical preparation is between 1 and 5mg/ml.
 4. Flexible impervious bag for medical use containing apharmaceutical preparation of oxaliplatinum according to claim 1,wherein said solution has a pH of 4.5 to 6.0, a concentration ofoxaliplatinum in the preparation of at least 95% of the initialconcentration, as well as a clear, colourless appearance free fromprecipitate after storage for a pharmaceutically acceptable period. 5.Flexible impervious bag for medical use containing a pharmaceuticalpreparation of oxaliplatinum, wherein said bag consists of a materialcomprising 70% polypropylene and 30% 11-amino-undecanoic acid.